Planet Biotechnology Inc. (PBI) is developing a therapeutic recombinant protein, PBI-220, that neutralizes anthrax toxin in vitro and protects against inhalational anthrax in vivo. PBI uses transgenic plants as an innovative, economical and flexible production technology. Our therapeutic protein, a fusion of the high- affinity human anthrax toxin receptor CMG2 and the Fc portion of IgG, offers broad-spectrum protection against anthrax because it can neutralize not only wild-type anthrax toxin, but toxin forms that have been modified to avoid neutralization by monoclonal antibodies. We believe that PBI-220 may be the 'best in class' therapeutic in development for anthrax. We have demonstrated the in vitro toxin-neutralizing potency of PBI-220, using a standard assay, to be as high as the best anti-PA antibodies under development by Avanir, Elusys or Human Genome Sciences. A dose of PBI-220 as low as 2 mg/kg was sufficient to completely protect rabbits challenged with >100 LD50 of B. anthracis spores. We have created transgenic tobacco plants that accumulate PBI-220 at commercially useful levels (>75 mg/kg fresh weight of leaves) and are scaling up our purification procedure. We propose to advance the development of PBI-220 beyond efficacy testing in rabbits to efficacy testing in a non-human primate (NHP) model of inhalational anthrax. These experiments will determine the dose, route of administration and timing of PBI-220 treatment that will provide protection at the maximum delay after spore inhalation, during periods when antibiotic alone becomes ineffective. We will evaluate the pharmacokinetics of PBI-220 in NHP, to help determine appropriate dosing in people. We will conduct pilot toxicology studies in rats and NHP to demonstrate PBI-220's safety. All of these studies are designed to support eventual filing of an Investigational New Drug Application with FDA for PBI-220, and its licensure under the FDA Animal Rule. An important aspect of the product development this grant will support is optimization of our manufacturing process and implementation of a Quality System so that we can produce PBI-220 under current Good Manufacturing Practices. PUBLIC HEALTH RELEVANCE: The American public is vulnerable to a bioterrorist attack using Anthrax (Bacillus anthracis). We believe than an immunoadhesin, comprised of the human anthrax toxin receptor CMG2 and a human IgG or IgA Fc, can provide complete protection against anthrax after the development of symptoms, without the need for vaccination, and would allow the development of the body's own protective antibodies against Bacillus anthracis.